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The effect of ACPD on the responses to NMDA and AMPA varies with layer in slices of rat visual cortex
Brain Research 812 Ž1998. 186–192
Research report
The effect of ACPD on the responses to NMDA and AMPA varies with layer in slices of rat visual cortex Xue-Feng Wang, Nigel W. Daw ) , Xiao-tao Jin Department of Ophthalmology and Visual Science, Yale UniÕersity School of Medicine, 330 Cedar Street, New HaÕen, CT 06520-8061, USA Accepted 15 September 1998
Abstract The effect of 1S,3 R-aminocyclopentane dicarboxylic acid ŽACPD. was measured on cells from various layers in slices of the rat visual cortex using whole-cell recording techniques. The position of the recorded cell was estimated by distance from pia to the layer VIrwhite matter boundary, and verified in 34r97 cells by staining with biocytin. Potentiation or depression of the responses to NMDA and AMPA by the metabotropic glutamate agonist ACPD was examined by iontophoresis of the drugs close to the cell body. Iontophoresis of ACPD had different effects in different layers. In layer VI, ACPD produced a substantial depolarization, which augmented the responses to NMDA and AMPA. In layer V, ACPD did not produce a significant depolarization, but potentiated the response to NMDA and AMPA. In layer IV, ACPD produced a small hyperpolarization, and depressed the response to NMDA. In layers II and III, the results were small and variable. Most recordings from stained cells were from pyramidal cells. Where recordings from non-pyramidal cells were obtained Ž3r34., results were the same as from pyramidal cells in the same layer. The same results were obtained when tetrodotoxin was in the bath solution. We conclude that the potentiation or depression of the response to NMDA and AMPA by ACPD varies with layer in rat visual cortex. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Visual cortex; Metabotropic glutamate receptor; Rat
1. Introduction We have previously shown that the metabotropic glutamate agonist 1S,3 R-aminocyclopentane dicarboxylic acid ŽACPD. potentiates the response to NMDA and AMPA in layer V cells recorded from slices of rat visual cortex w44x. This potentiation occurred within a few seconds, and lasted a few minutes. It was a postsynaptic phenomenon, since it was abolished by Guanosine 5X-O-Ž2-thiodiphosphate. ŽGDB-b-S. in the pipette solution, and remained with tetrodotoxin in the bath solution. In most work in other parts of the nervous system, ACPD potentiates the response to NMDA. This is true in hippocampus w1,20x, cerebellum w25x, spinal cord w6,9x, olfactory cortex w10x, neocortex w34x, striatum w33x and Xenopus oocytes expressing NMDA receptors w24x. However, results with AMPA are variable. In addition, in some
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systems, ACPD depresses the response to NMDA w11,20,29,46x. It seems likely that the results in the visual cortex could vary with layer. Experiments on slices of rat and guinea pig cortex show that ACPD leads to a depolarization, and a transition from a burst firing mode to a tonic firing mode in layer V w45x. There is also an increase in the number of action potentials elicited during a depolarizing current pulse w17x. On the other hand, both excitatory and inhibitory components of the postsynaptic currents ŽPSCs. are reduced in layers II and III w7x. Moreover, The effect of ACPD on spontaneous activity in the cat visual cortex varies with layer, with reductions in layers IIrIII, increases in layers VrVI, and variable results in layer IV w38x. Thus both excitatory and inhibitory effects are found, in different layers of cerebral cortex. If the potentiation of the responses to NMDA and AMPA are related to these cellular effects, then one would expect the potentiation to vary with layer, and possibly even be a depression in some layers. We therefore decided to test the point, using whole-cell recording in slices of rat visual cortex.
0006-8993r98r$ - see front matter q 1998 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 8 . 0 1 0 0 0 - 2
X.-F. Wang et al.r Brain Research 812 (1998) 186–192
2. Materials and methods Coronal slices were made of rat visual cortex as described previously w14,44x A 2–4 week old rat was anesthetized with sodium pentobarbital Ž50 mgrkg. then perfused through the heart with an ice-cold solution consisting of sucrose—256 mM, KCl 2.5—mM, MgSO4 —2 mM, NaH 2 PO4 —1.25 mM, glucose—10 mM, NaHCO 3 26— mM and CaCl 2 —2 mM at pH 7.3. The brain was removed and attached to a dish with superglue, and kept in the same ice-cold solution gassed with 95% O 2 , 5% CO 2 . Slices were then cut at 400 mm on a vibratome, and stored at room temperature in a chamber containing artificial cerebrospinal fluid ŽACSF. consisting of NaCl—128 mM, KCl —2.5 mM, MgSO4 —2 mM, NaH 2 PO4 —1.25 mM, glucose—10 mM, NaHCO 3 —26 mM, and CaCl 2 —2 mM at pH 7.3 with 95% O 2 , 5% CO 2 bubbling through it. For recording, a slice was transferred to a perfusion chamber and held between two pieces of net. The perfusion solution was ACSF. The solution was heated to 33–358C in its reservoir, and again by a heat exchanger
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next to the perfusion chamber. Flow rate was 3 mlrmin. Whole cell electrodes were pulled on a Sutter Instruments P-87 pipette puller and filled with K-methanesulfonate— 125.0 mM, NaCl—5.0 mM, MgCl 2 —1.0 mM, CaCl 2 —1.0 mM, EGTA—10.0 mM, HEPES—10.0 mM, K 2 ATP—5 mM, tris salt GTP—1.0 mM or GDP-b-S—1.0 mM, and 1% biocytin at pH 7.30. Most electrodes had a resistance of 6–9 M V. Recordings were made ‘blind’ w5x, using an Axoclamp 2A amplifier ŽAxon Instr., Burlingame, CA.. The electrode was advanced through the tissue under positive pressure in voltage clamp, with a 10 mV pulse applied to it every 10–20 ms, until a small increase in resistance was seen. Pressure was then released and suction applied until the seal resistance exceeded 1 GV. Further suction ruptured the cell membrane to give recordings in the whole-cell configuration. The recording electrode was placed at a particular distance between pial surface and white matter, to record from cells in a particular layer. Measuring from the pia, the boundaries are at 10% for IrII, 32–36% for IIIrIV, 47–52% for IVrV, and 72–75% for VrVI, independent
Fig. 1. Potentiation and depression of NMDA and AMPA responses by ACPD in various layers of visual cortex. For each set of records, the first line shows the response to iontophoresis of NMDA; second line ACPD; third line NMDAq ACPD; fourth line AMPA; fifth line AMPAq ACPD; and sixth line the time course. Hyperpolarizing pulses were delivered to measure input resistance of the cell. ŽA. records from a cell in layer V; ŽB. a pyramidal cell in layer VI; ŽC. a fusiform cell in layer VI; ŽD. a pyramidal cell in layer IV; ŽE. a stellate cell in layer IV; and ŽF. a cell in layers IIrIII.
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of whether one is in monocular or binocular parts of visual cortex w36x. A multiple barrel iontophoretic electrode was then inserted to the same depth in the tissue near the cell body. The iontophoretic electrode contained 20 mM NMDA, 20 mM AMPA and 50 mM ACPD ŽpH 7.4–7.8. in different barrels Žretaining current q10 nA, ejecting current y50 nA for ACPD, and 10 nA above threshold for both NMDA and AMPA.. Records were taken for each cell as follows, with intervals in general of 90 s between applications: first application of NMDA several times to check the consistency of the response, then application of AMPA, then application of ACPD, then a longer interval of 2 min, then application of ACPD and NMDA together, then a longer interval of about 3 min, then application of ACPD and AMPA together, then a longer interval of about 3 min, then application of NMDA and AMPA separately to observe recovery. The longer intervals were used to avoid residual effects from one application from interfering with the next. If the membrane potential was not stable, or another level of iontophoretic current was desirable, the whole procedure was repeated. Data was acquired and analyzed using pCLAMP software ŽAxon Instr... Results were quantified by measuring the area under the depolarization from NMDA or AMPA in the presence of ACPD, divided by the area under the depolarization from NMDA or AMPA alone Results are presented as mean " S.D., and significance evaluated by Student’s t-test. To verify the laminar location of the cells, and to determine if pyramidal or non-pyramidal cells were being recorded, a sample of 34r97 cells was recorded with biocytin in the whole cell pipette. The slice was then removed, placed between two pieces of filter paper, and fixed overnight in 4% paraformaldehyde. It was then sectioned at 80 mm on a freezing microtome, and reacted by the avidin–biotin–peroxidase method to reveal the cell morphology w22x. ACPD, AMPA and APV were obtained from Research Biochemicals ŽNatick, MA., Ž RS .-a-methyl-4-carbo-
xyphenylglycine ŽMCPG. from Tocris Cookson ŽSt. Louis, MO. and all other chemicals from Sigma ŽSt. Louis, MO..
3. Results As described previously w44x, responses of cells in layer V were potentiated by the application of ACPD ŽFig. 1A, Fig. 2A.. In this cell, ACPD produced a slight depolarization by itself. However, the response to ACPD iontophoresed at the same time as NMDA was considerably larger than the response to NMDA by itself, showing potentiation. In this particular case, the potentiation of the response to AMPA was not large. A total of 29 cells were recorded from layer V. Potentiation was measured by comparing the area under the curve in response to NMDA q ACPD Žhereafter called the response. with the area under the curve for NMDA by itself. The response to NMDA was potentiated by a factor 1.96 " 0.96 Žmean " S.D.. that represents a significant increase Ž t-test, P 0.001, n s 29.. Potentiation of the response to AMPA was 1.61 " 0.83 Ž P - 0.001, n s 28.. Depolarization produced by ACPD was 0.66 " 2.2 mV Ž P s 0.144, n s 25.. In layer VI, a rather different result was obtained ŽFig. 1B, Fig. 2B.. The response to NMDAq ACPD was clearly larger than the response to NMDA by itself, and the response to AMPAq ACPD was larger than the response to AMPA by itself. However, ACPD by itself frequently produced a depolarization. In the two cells illustrated, this depolarization was sufficient to produce action potentials. Measurement of the depolarization produced by ACPD in 19 cells in layer VI was 9.41 " 7.22 mV Ž P - 0.01, n s 19.. In the example shown in Fig. 1B, the depolarization produced by ACPD was actually larger than the depolarizations produced by NMDA and AMPA. While the latency for the ACPD response was long, it accentuated the responses to NMDA and AMPA that occurred earlier. This cell was a pyramidal cell ŽFig. 2B.. A similar result was seen in a non-pyramidal cell in the same layer
Fig. 2. Biocytin stains of the cells whose records are shown in Fig. 1.
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ŽFig. 1C, Fig. 2C.. Thus the results in layer VI did not represent a potentiation, rather they represented a significant depolarization by ACPD which augmented the depolarizations produced by NMDA and AMPA. The depressive effect of ACPD seen in layer IV is illustrated by Fig. 1D, Fig. 2D. ACPD produced a small hyperpolarization by itself. ACPD reduced the response to NMDA, and also the response to AMPA. This was a pyramidal cell, and depressive effects were also seen in a stellate cell in the same layer ŽFig. 1E, Fig. 2E.. The stellate cell was fast-spiking w13x, and the response to NMDA was again reduced, but the response to AMPA was not. Fourteen cells we re recorded in layer IV. A small but significant hyperpolarization was seen Ž1.15 " 1.4 mV; P s 0.012, n s 14.. The response to NMDA was always reduced, by a significant factor Ž0.44 " 0.28; P - 0.001, n s 14., while the response to AMPA was not reduced significantly Ž0.88 " 0.52; P s 0.41, n s 14.. Results in layers IIrIII were more variable. On average, the response to NMDA was not changed significantly by
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iontophoresis of ACPD at the same time Ž1.03 " 0.76; P s 0.8, n s 32., nor was the response to AMPA Ž1.08 " 0.5; P s 0.38, n s 32.. In the example shown in Fig. 1F, Fig. 2F, the response to NMDA was reduced, while the response to AMPA was not. Membrane potential was measured, to see if the differences in the effect of ACPD with layer could be accounted for by its variation. Mean resting potential for cells in layer VI was y62 mV, for cells in layer V was y62.7 mV, and for cells in layer IV was y62.9 mV. It seems most unlikely that the large differences in the effect of ACPD between layers IV, V and VI could be accounted for by these small differences in resting potential. Mean resting potential in layers IIrIII was rather higher Žy72.7 mV.. However, iontophoresis of ACPD in this layer did not give a distinct result, and the result was not correlated with resting potential in this or any other layer. Changes in input resistance were measured, to see if ACPD led to a closing of channels, or an opening of channels, in the postsynaptic cell. There was a significant
Fig. 3. Effects of ACPD on the response to NMDA with TTX in the bath solution.
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increase in resistance for cells in layer VI Ž12 " 7.5%; P - 0.001. and in layer IV Ž12 " 8.4%; P - 0.001.. The increases seen in layer V Ž6.8 " 17%; P s 0.19. and layers IIrIII Ž5 " 18%; P s 0.14. were not significant. We have previously shown that the potentiation found in layer V is postsynaptic, since it is abolished when GDB-b-S is included in the pipette solution w44x. The depolarization produced by ACPD in layer VI was also abolished by GDB-b-S. Five cells were tested, with a depolarization of 0.8 " 0.45 mV in the presence of GDBb-S, compared to a depolarization of 5.2 " 3.5 mV using normal intracellular solution, which was significantly different Ž P - 0.05.. This effect of ACPD is therefore also postsynaptic. Six cells were also tested in layer IV with GDB-b-S in the pipette solution. The results were complicated, suggesting both pre- and postsynaptic effects. As a further test of whether the effects were pre- or postsynaptic, 24 cells were recorded with 0.5–1 mM tetrodotoxin in the bath solution to abolish action potentials. An example from each layer is shown in Fig. 3, and the change in the response to NMDA for each cell summarised in Fig. 4. ACPD had little effect on membrane potential, input impedance, or the response to NMDA in layer IIrIII cells. In layer IV cells, ACPD hyperpolarized the membrane by 4.5 " 1.6 mV Ž P s 0.004, n s 5., reduced the resistance by 15 " 10.4% Ž P - 0.001., and reduced the response to NMDA by 40 " 20% Ž P s 0.005.. In layer V cells, ACPD increased the NMDA response by a factor of 2.3 " 1.2 Ž P s 0.035, n s 7.. In five cells, there was little change in membrane potential or input resistance. In two cells, the membrane potential was depolarized Ž2.5 and 7 mV. and the input resistance was increased Ž11 and 14%.. In layer VI cells, ACPD produced a depolarization in 5r7 cells Ž5.4 " 3.4 mV., increased the input resistance in 4r7 cells Ž16.8 " 8.9%., and the response to ACPD added to the response to NMDA to make the response to NMDA much more long-lasting. We have also previously shown that the potentiation of the response to NMDA by ACPD is abolished by MCPG
Fig. 4. Response to NMDA in the presence of ACPD compared to the response to NMDA by itself for 24 cells in various layers with TTX in the bath solution.
in layer V cells w44x. The depolarization produced by ACPD in layer VI cells was also abolished by 1 mM MCPG in the bath solution Ždata not shown..
4. Discussion Using whole-cell recordings, we found that the effect of ACPD application is layer-specific. Facilitatory effects are found in infragranular layers of cortex, with significant depolarization in most cells in layer VI, but without significant depolarization in most cells in layer V. Depressive effects are found with hyperpolarization in layer IV; and no consistent effects are found in layers II and III. Clearly, ACPD is activating different mechanisms in different layers. Any conductances affected by ACPD in layer V are likely to be voltage-dependent, since ACPD did not change membrane potential or input resistance significantly w3,12,32,39x. Alternatively, metabotropic glutamate receptors may affect NMDA receptors by phosphorylation of the receptor through protein kinase C w26,30,42x or cAMP-dependent protein kinase w35x. Potentiation of the NMDA response by ACPD has been shown to depend on protein kinase C in some preparations w1,10,24x. In layer VI, on the other hand, ACPD clearly closed channels that are active at resting potential, since ACPD produced both depolarization and an increase in input resistance. The mechanism for the depressive effects seen in layer IV remains to be worked out. Presynaptic inhibitory effects have been demonstrated in hippocampus w2,16x, striatum w27x, and visual cortical neurons in layers IV–VI w41x. A postsynaptic opening of Kq channels can also lead to depressive effects w15,18x. This is consistent with our results in TTX, where ACPD produced a hyperpolarization with a reduction in input resistance. However, in the absence of TTX, an increase in resistance was seen. Our conclusion is that more than one mechanism is involved in this layer, and that further sets of experiments using selective agonists for specific groups of metabotropic glutamate receptors andror cells isolated and identified from particular layers of cortex will be required to analyze them. Interestingly, a recent paper recording from cultured cells from mouse neocortex showed a reduction in the NMDA current from activation of Group I metabotropic glutamate receptors w46x, in contrast to the increase that is seen in most preparations. The tentative explanation provided by the authors for this result was that the effect of metabotropic glutamate receptors on NMDA currents depends on the subunit composition of the NMDA receptor w40x, which may vary from one cell type to another. If this is the correct explanation, and rat neocortex is like mouse neocortex, then our work predicts that the cells that survived in culture from mouse neocortex were mostly from layer IV, and that the NMDA receptor subunit composition
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in layer IV is different from the subunit composition in layers V and VI. It is interesting to compare the results in this paper with those from iontophoresis of ACPD in intact animals. Results have been obtained on responses from neurons in the somatosensory cortex of rat w8x, and neurons in the visual cortex of cat w38,43x, and they are similar. The sensory response is depressed in all layers, most strongly in superficial layers. Spontaneous activity is depressed in supragranular layers, but increased in infragranular layers. Thus the facilitatory effect of ACPD on NMDA and AMPA is reflected in the effect on spontaneous activity in the intact animal, but not on the effect on the visual response. There are also differences between the in vivo results from cat and the in vitro results from rat in superficial layers. The main depressive effect seen in cat visual cortex occurred in layers IIrIII, while results in layer IV were ambiguous w38x. The main depressive effect seen in rat visual cortex occurred in layer IV, while results in layers IIrIII were ambiguous. This could be a species difference. Depressive effects are associated with group II mGluRs w28x, and group II mGluRs are concentrated in layers IIrIII in the cat, but seem to be more concentrated in layer IV in the rat w31x. In summary, this work clearly shows that there is a variety of ways in which metabotropic glutamate receptors influence responses in the visual cortex. Suggestions have been made that metabotropic glutamate receptors may influence plasticity in the visual cortex, through the phosphoinositides, andror through cyclic AMP w4,37x. Suggestions have also been made that mGluRs may affect longterm depression rather than long-term potentiation w19,21,23x. Our work shows that these suggestions need to be analyzed by layer before they can be placed on a firm footing.
Acknowledgements This work was supported by Public Health Service grant RO1 EY11353.
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Research report
The effect of ACPD on the responses to NMDA and AMPA varies with layer in slices of rat visual cortex Xue-Feng Wang, Nigel W. Daw ) , Xiao-tao Jin Department of Ophthalmology and Visual Science, Yale UniÕersity School of Medicine, 330 Cedar Street, New HaÕen, CT 06520-8061, USA Accepted 15 September 1998
Abstract The effect of 1S,3 R-aminocyclopentane dicarboxylic acid ŽACPD. was measured on cells from various layers in slices of the rat visual cortex using whole-cell recording techniques. The position of the recorded cell was estimated by distance from pia to the layer VIrwhite matter boundary, and verified in 34r97 cells by staining with biocytin. Potentiation or depression of the responses to NMDA and AMPA by the metabotropic glutamate agonist ACPD was examined by iontophoresis of the drugs close to the cell body. Iontophoresis of ACPD had different effects in different layers. In layer VI, ACPD produced a substantial depolarization, which augmented the responses to NMDA and AMPA. In layer V, ACPD did not produce a significant depolarization, but potentiated the response to NMDA and AMPA. In layer IV, ACPD produced a small hyperpolarization, and depressed the response to NMDA. In layers II and III, the results were small and variable. Most recordings from stained cells were from pyramidal cells. Where recordings from non-pyramidal cells were obtained Ž3r34., results were the same as from pyramidal cells in the same layer. The same results were obtained when tetrodotoxin was in the bath solution. We conclude that the potentiation or depression of the response to NMDA and AMPA by ACPD varies with layer in rat visual cortex. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Visual cortex; Metabotropic glutamate receptor; Rat
1. Introduction We have previously shown that the metabotropic glutamate agonist 1S,3 R-aminocyclopentane dicarboxylic acid ŽACPD. potentiates the response to NMDA and AMPA in layer V cells recorded from slices of rat visual cortex w44x. This potentiation occurred within a few seconds, and lasted a few minutes. It was a postsynaptic phenomenon, since it was abolished by Guanosine 5X-O-Ž2-thiodiphosphate. ŽGDB-b-S. in the pipette solution, and remained with tetrodotoxin in the bath solution. In most work in other parts of the nervous system, ACPD potentiates the response to NMDA. This is true in hippocampus w1,20x, cerebellum w25x, spinal cord w6,9x, olfactory cortex w10x, neocortex w34x, striatum w33x and Xenopus oocytes expressing NMDA receptors w24x. However, results with AMPA are variable. In addition, in some
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systems, ACPD depresses the response to NMDA w11,20,29,46x. It seems likely that the results in the visual cortex could vary with layer. Experiments on slices of rat and guinea pig cortex show that ACPD leads to a depolarization, and a transition from a burst firing mode to a tonic firing mode in layer V w45x. There is also an increase in the number of action potentials elicited during a depolarizing current pulse w17x. On the other hand, both excitatory and inhibitory components of the postsynaptic currents ŽPSCs. are reduced in layers II and III w7x. Moreover, The effect of ACPD on spontaneous activity in the cat visual cortex varies with layer, with reductions in layers IIrIII, increases in layers VrVI, and variable results in layer IV w38x. Thus both excitatory and inhibitory effects are found, in different layers of cerebral cortex. If the potentiation of the responses to NMDA and AMPA are related to these cellular effects, then one would expect the potentiation to vary with layer, and possibly even be a depression in some layers. We therefore decided to test the point, using whole-cell recording in slices of rat visual cortex.
0006-8993r98r$ - see front matter q 1998 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 8 . 0 1 0 0 0 - 2
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2. Materials and methods Coronal slices were made of rat visual cortex as described previously w14,44x A 2–4 week old rat was anesthetized with sodium pentobarbital Ž50 mgrkg. then perfused through the heart with an ice-cold solution consisting of sucrose—256 mM, KCl 2.5—mM, MgSO4 —2 mM, NaH 2 PO4 —1.25 mM, glucose—10 mM, NaHCO 3 26— mM and CaCl 2 —2 mM at pH 7.3. The brain was removed and attached to a dish with superglue, and kept in the same ice-cold solution gassed with 95% O 2 , 5% CO 2 . Slices were then cut at 400 mm on a vibratome, and stored at room temperature in a chamber containing artificial cerebrospinal fluid ŽACSF. consisting of NaCl—128 mM, KCl —2.5 mM, MgSO4 —2 mM, NaH 2 PO4 —1.25 mM, glucose—10 mM, NaHCO 3 —26 mM, and CaCl 2 —2 mM at pH 7.3 with 95% O 2 , 5% CO 2 bubbling through it. For recording, a slice was transferred to a perfusion chamber and held between two pieces of net. The perfusion solution was ACSF. The solution was heated to 33–358C in its reservoir, and again by a heat exchanger
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next to the perfusion chamber. Flow rate was 3 mlrmin. Whole cell electrodes were pulled on a Sutter Instruments P-87 pipette puller and filled with K-methanesulfonate— 125.0 mM, NaCl—5.0 mM, MgCl 2 —1.0 mM, CaCl 2 —1.0 mM, EGTA—10.0 mM, HEPES—10.0 mM, K 2 ATP—5 mM, tris salt GTP—1.0 mM or GDP-b-S—1.0 mM, and 1% biocytin at pH 7.30. Most electrodes had a resistance of 6–9 M V. Recordings were made ‘blind’ w5x, using an Axoclamp 2A amplifier ŽAxon Instr., Burlingame, CA.. The electrode was advanced through the tissue under positive pressure in voltage clamp, with a 10 mV pulse applied to it every 10–20 ms, until a small increase in resistance was seen. Pressure was then released and suction applied until the seal resistance exceeded 1 GV. Further suction ruptured the cell membrane to give recordings in the whole-cell configuration. The recording electrode was placed at a particular distance between pial surface and white matter, to record from cells in a particular layer. Measuring from the pia, the boundaries are at 10% for IrII, 32–36% for IIIrIV, 47–52% for IVrV, and 72–75% for VrVI, independent
Fig. 1. Potentiation and depression of NMDA and AMPA responses by ACPD in various layers of visual cortex. For each set of records, the first line shows the response to iontophoresis of NMDA; second line ACPD; third line NMDAq ACPD; fourth line AMPA; fifth line AMPAq ACPD; and sixth line the time course. Hyperpolarizing pulses were delivered to measure input resistance of the cell. ŽA. records from a cell in layer V; ŽB. a pyramidal cell in layer VI; ŽC. a fusiform cell in layer VI; ŽD. a pyramidal cell in layer IV; ŽE. a stellate cell in layer IV; and ŽF. a cell in layers IIrIII.
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of whether one is in monocular or binocular parts of visual cortex w36x. A multiple barrel iontophoretic electrode was then inserted to the same depth in the tissue near the cell body. The iontophoretic electrode contained 20 mM NMDA, 20 mM AMPA and 50 mM ACPD ŽpH 7.4–7.8. in different barrels Žretaining current q10 nA, ejecting current y50 nA for ACPD, and 10 nA above threshold for both NMDA and AMPA.. Records were taken for each cell as follows, with intervals in general of 90 s between applications: first application of NMDA several times to check the consistency of the response, then application of AMPA, then application of ACPD, then a longer interval of 2 min, then application of ACPD and NMDA together, then a longer interval of about 3 min, then application of ACPD and AMPA together, then a longer interval of about 3 min, then application of NMDA and AMPA separately to observe recovery. The longer intervals were used to avoid residual effects from one application from interfering with the next. If the membrane potential was not stable, or another level of iontophoretic current was desirable, the whole procedure was repeated. Data was acquired and analyzed using pCLAMP software ŽAxon Instr... Results were quantified by measuring the area under the depolarization from NMDA or AMPA in the presence of ACPD, divided by the area under the depolarization from NMDA or AMPA alone Results are presented as mean " S.D., and significance evaluated by Student’s t-test. To verify the laminar location of the cells, and to determine if pyramidal or non-pyramidal cells were being recorded, a sample of 34r97 cells was recorded with biocytin in the whole cell pipette. The slice was then removed, placed between two pieces of filter paper, and fixed overnight in 4% paraformaldehyde. It was then sectioned at 80 mm on a freezing microtome, and reacted by the avidin–biotin–peroxidase method to reveal the cell morphology w22x. ACPD, AMPA and APV were obtained from Research Biochemicals ŽNatick, MA., Ž RS .-a-methyl-4-carbo-
xyphenylglycine ŽMCPG. from Tocris Cookson ŽSt. Louis, MO. and all other chemicals from Sigma ŽSt. Louis, MO..
3. Results As described previously w44x, responses of cells in layer V were potentiated by the application of ACPD ŽFig. 1A, Fig. 2A.. In this cell, ACPD produced a slight depolarization by itself. However, the response to ACPD iontophoresed at the same time as NMDA was considerably larger than the response to NMDA by itself, showing potentiation. In this particular case, the potentiation of the response to AMPA was not large. A total of 29 cells were recorded from layer V. Potentiation was measured by comparing the area under the curve in response to NMDA q ACPD Žhereafter called the response. with the area under the curve for NMDA by itself. The response to NMDA was potentiated by a factor 1.96 " 0.96 Žmean " S.D.. that represents a significant increase Ž t-test, P 0.001, n s 29.. Potentiation of the response to AMPA was 1.61 " 0.83 Ž P - 0.001, n s 28.. Depolarization produced by ACPD was 0.66 " 2.2 mV Ž P s 0.144, n s 25.. In layer VI, a rather different result was obtained ŽFig. 1B, Fig. 2B.. The response to NMDAq ACPD was clearly larger than the response to NMDA by itself, and the response to AMPAq ACPD was larger than the response to AMPA by itself. However, ACPD by itself frequently produced a depolarization. In the two cells illustrated, this depolarization was sufficient to produce action potentials. Measurement of the depolarization produced by ACPD in 19 cells in layer VI was 9.41 " 7.22 mV Ž P - 0.01, n s 19.. In the example shown in Fig. 1B, the depolarization produced by ACPD was actually larger than the depolarizations produced by NMDA and AMPA. While the latency for the ACPD response was long, it accentuated the responses to NMDA and AMPA that occurred earlier. This cell was a pyramidal cell ŽFig. 2B.. A similar result was seen in a non-pyramidal cell in the same layer
Fig. 2. Biocytin stains of the cells whose records are shown in Fig. 1.
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ŽFig. 1C, Fig. 2C.. Thus the results in layer VI did not represent a potentiation, rather they represented a significant depolarization by ACPD which augmented the depolarizations produced by NMDA and AMPA. The depressive effect of ACPD seen in layer IV is illustrated by Fig. 1D, Fig. 2D. ACPD produced a small hyperpolarization by itself. ACPD reduced the response to NMDA, and also the response to AMPA. This was a pyramidal cell, and depressive effects were also seen in a stellate cell in the same layer ŽFig. 1E, Fig. 2E.. The stellate cell was fast-spiking w13x, and the response to NMDA was again reduced, but the response to AMPA was not. Fourteen cells we re recorded in layer IV. A small but significant hyperpolarization was seen Ž1.15 " 1.4 mV; P s 0.012, n s 14.. The response to NMDA was always reduced, by a significant factor Ž0.44 " 0.28; P - 0.001, n s 14., while the response to AMPA was not reduced significantly Ž0.88 " 0.52; P s 0.41, n s 14.. Results in layers IIrIII were more variable. On average, the response to NMDA was not changed significantly by
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iontophoresis of ACPD at the same time Ž1.03 " 0.76; P s 0.8, n s 32., nor was the response to AMPA Ž1.08 " 0.5; P s 0.38, n s 32.. In the example shown in Fig. 1F, Fig. 2F, the response to NMDA was reduced, while the response to AMPA was not. Membrane potential was measured, to see if the differences in the effect of ACPD with layer could be accounted for by its variation. Mean resting potential for cells in layer VI was y62 mV, for cells in layer V was y62.7 mV, and for cells in layer IV was y62.9 mV. It seems most unlikely that the large differences in the effect of ACPD between layers IV, V and VI could be accounted for by these small differences in resting potential. Mean resting potential in layers IIrIII was rather higher Žy72.7 mV.. However, iontophoresis of ACPD in this layer did not give a distinct result, and the result was not correlated with resting potential in this or any other layer. Changes in input resistance were measured, to see if ACPD led to a closing of channels, or an opening of channels, in the postsynaptic cell. There was a significant
Fig. 3. Effects of ACPD on the response to NMDA with TTX in the bath solution.
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increase in resistance for cells in layer VI Ž12 " 7.5%; P - 0.001. and in layer IV Ž12 " 8.4%; P - 0.001.. The increases seen in layer V Ž6.8 " 17%; P s 0.19. and layers IIrIII Ž5 " 18%; P s 0.14. were not significant. We have previously shown that the potentiation found in layer V is postsynaptic, since it is abolished when GDB-b-S is included in the pipette solution w44x. The depolarization produced by ACPD in layer VI was also abolished by GDB-b-S. Five cells were tested, with a depolarization of 0.8 " 0.45 mV in the presence of GDBb-S, compared to a depolarization of 5.2 " 3.5 mV using normal intracellular solution, which was significantly different Ž P - 0.05.. This effect of ACPD is therefore also postsynaptic. Six cells were also tested in layer IV with GDB-b-S in the pipette solution. The results were complicated, suggesting both pre- and postsynaptic effects. As a further test of whether the effects were pre- or postsynaptic, 24 cells were recorded with 0.5–1 mM tetrodotoxin in the bath solution to abolish action potentials. An example from each layer is shown in Fig. 3, and the change in the response to NMDA for each cell summarised in Fig. 4. ACPD had little effect on membrane potential, input impedance, or the response to NMDA in layer IIrIII cells. In layer IV cells, ACPD hyperpolarized the membrane by 4.5 " 1.6 mV Ž P s 0.004, n s 5., reduced the resistance by 15 " 10.4% Ž P - 0.001., and reduced the response to NMDA by 40 " 20% Ž P s 0.005.. In layer V cells, ACPD increased the NMDA response by a factor of 2.3 " 1.2 Ž P s 0.035, n s 7.. In five cells, there was little change in membrane potential or input resistance. In two cells, the membrane potential was depolarized Ž2.5 and 7 mV. and the input resistance was increased Ž11 and 14%.. In layer VI cells, ACPD produced a depolarization in 5r7 cells Ž5.4 " 3.4 mV., increased the input resistance in 4r7 cells Ž16.8 " 8.9%., and the response to ACPD added to the response to NMDA to make the response to NMDA much more long-lasting. We have also previously shown that the potentiation of the response to NMDA by ACPD is abolished by MCPG
Fig. 4. Response to NMDA in the presence of ACPD compared to the response to NMDA by itself for 24 cells in various layers with TTX in the bath solution.
in layer V cells w44x. The depolarization produced by ACPD in layer VI cells was also abolished by 1 mM MCPG in the bath solution Ždata not shown..
4. Discussion Using whole-cell recordings, we found that the effect of ACPD application is layer-specific. Facilitatory effects are found in infragranular layers of cortex, with significant depolarization in most cells in layer VI, but without significant depolarization in most cells in layer V. Depressive effects are found with hyperpolarization in layer IV; and no consistent effects are found in layers II and III. Clearly, ACPD is activating different mechanisms in different layers. Any conductances affected by ACPD in layer V are likely to be voltage-dependent, since ACPD did not change membrane potential or input resistance significantly w3,12,32,39x. Alternatively, metabotropic glutamate receptors may affect NMDA receptors by phosphorylation of the receptor through protein kinase C w26,30,42x or cAMP-dependent protein kinase w35x. Potentiation of the NMDA response by ACPD has been shown to depend on protein kinase C in some preparations w1,10,24x. In layer VI, on the other hand, ACPD clearly closed channels that are active at resting potential, since ACPD produced both depolarization and an increase in input resistance. The mechanism for the depressive effects seen in layer IV remains to be worked out. Presynaptic inhibitory effects have been demonstrated in hippocampus w2,16x, striatum w27x, and visual cortical neurons in layers IV–VI w41x. A postsynaptic opening of Kq channels can also lead to depressive effects w15,18x. This is consistent with our results in TTX, where ACPD produced a hyperpolarization with a reduction in input resistance. However, in the absence of TTX, an increase in resistance was seen. Our conclusion is that more than one mechanism is involved in this layer, and that further sets of experiments using selective agonists for specific groups of metabotropic glutamate receptors andror cells isolated and identified from particular layers of cortex will be required to analyze them. Interestingly, a recent paper recording from cultured cells from mouse neocortex showed a reduction in the NMDA current from activation of Group I metabotropic glutamate receptors w46x, in contrast to the increase that is seen in most preparations. The tentative explanation provided by the authors for this result was that the effect of metabotropic glutamate receptors on NMDA currents depends on the subunit composition of the NMDA receptor w40x, which may vary from one cell type to another. If this is the correct explanation, and rat neocortex is like mouse neocortex, then our work predicts that the cells that survived in culture from mouse neocortex were mostly from layer IV, and that the NMDA receptor subunit composition
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in layer IV is different from the subunit composition in layers V and VI. It is interesting to compare the results in this paper with those from iontophoresis of ACPD in intact animals. Results have been obtained on responses from neurons in the somatosensory cortex of rat w8x, and neurons in the visual cortex of cat w38,43x, and they are similar. The sensory response is depressed in all layers, most strongly in superficial layers. Spontaneous activity is depressed in supragranular layers, but increased in infragranular layers. Thus the facilitatory effect of ACPD on NMDA and AMPA is reflected in the effect on spontaneous activity in the intact animal, but not on the effect on the visual response. There are also differences between the in vivo results from cat and the in vitro results from rat in superficial layers. The main depressive effect seen in cat visual cortex occurred in layers IIrIII, while results in layer IV were ambiguous w38x. The main depressive effect seen in rat visual cortex occurred in layer IV, while results in layers IIrIII were ambiguous. This could be a species difference. Depressive effects are associated with group II mGluRs w28x, and group II mGluRs are concentrated in layers IIrIII in the cat, but seem to be more concentrated in layer IV in the rat w31x. In summary, this work clearly shows that there is a variety of ways in which metabotropic glutamate receptors influence responses in the visual cortex. Suggestions have been made that metabotropic glutamate receptors may influence plasticity in the visual cortex, through the phosphoinositides, andror through cyclic AMP w4,37x. Suggestions have also been made that mGluRs may affect longterm depression rather than long-term potentiation w19,21,23x. Our work shows that these suggestions need to be analyzed by layer before they can be placed on a firm footing.
Acknowledgements This work was supported by Public Health Service grant RO1 EY11353.
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